Radiochemische Untersuchungen zur Proteinbindung und Knochenmetastasenaffinität von Y(III)-Komplexen

Neumaier, Bernd

Book/Report

FZJ-2019-01460

Radiochemische Untersuchungen zur Proteinbindung und Knochenmetastasenaffinität von Y(III)-Komplexen

Neumaier, B. (Corresponding author)FZJ*

1996
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag Jülich

Jülich : Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag, Berichte des Forschungszentrums Jülich 3236, 111 p. (1996)

Please use a persistent id in citations: http://hdl.handle.net/2128/21644

Report No.: Juel-3236

Abstract: $^{90}$y is used routinely for different radiotherapeutic applications like radiosynoviorthesis and palliative therapy of multiple bone metastases. But detailed information on the biochemical pathways of cationic and complexed radiometal is still missing and prevents a full utilization of its therapeutic potential. The experiments here focus on the binding of radioyttrium (either in the form of no carrier added $^{88}$y and $^{86}$y, or as carrier added tracer using given amounts of $^{nat}$Y(III))to blood constituents. Systematic studies on the binding of radioyttrium to human serum albumin (HSA) as a model serum protein were carried out by gel-(GF) and ultrafiltration (UF). Binding of radioyttrium to HSA is low (5% determined by GF and 20 % by UF) in the presence of many endogenous anions (Cr, NO$_{3}$-, F, HCO$_{3}^{-}$- and OH') but increases significantly in the case of phosphate (80% (GF) and 95% (UF)). On the other hand the phosphate anion was bound significantly to HSA only in the presence of yttrium as was determined with $^{32}$p labelled phosphate. An analysis of this ternary system showed that yttrium and phosphate are bound simultaneously to HSA in a stoichometric ratio of 1:1. The formation constant of the postulated ternary complex was estimated to be log$\beta$ = 10.9 (l = 0.15 M; T = 25°C) determined by competitive experiments. Concerning the chemical mode of this binding, the carboxylate groups of the peptidechain were found to be responsible for the binding of $^{88}$Y and [$^{32}$P]PO$_{4}^{3-}$ 3- to serum proteins as was deduced from studies with homopolyaminoacids. The number of binding sites for Y(III) and PO$_{4}^{3-}$ on HSA and apo-transferrin was determined to be 14 or 7 which suprisingly corresponds exactly to the number of vicinal aspartic and glutamic acids in the two peptide chains of the serum proteins. Although all experimental correlations strongly speak in favour of a ternary complex formation, a colloidal system stabilized by macromolecular polyelectrolyts cannot be completely excluded. An extension of the studies to other trivalent metals showed that the tendency to build a ternary complex is a function of their ionic radii. Whereas light and transition lanthanides with large radii have a distinct inclination toward the building of a ternary compound, this becomes lower when the radius of the metal decreases. Moreover, when the radius decreases further as in the case of metals of the III main group, no such ternary compound can be observed. This tendency deduced by indirect measurements with [$^{32}P]PO_{4}^{3-}$ 3-could be confirmed in binding studies with $^{67}$Ga, $^{139}$Ce, $^{143}$Pm, $^{145}$Sm, $^{159}$Dy, $^{169}$Yb and $^{173}$Lu. The results obtained for the in vitro model were transferred to medical studies in order to analyse the in vivo behavior of radioyttrium in animal experiments and PET-studies (the latter using the $\beta^{+}$ emitting $^{86}$Y) with patients suffering from multiple bone metastases: after i.v. application of n.c.a. yttrium either as citrate or EDTMP complex the fate of the metal-ion depends on the stability of the injected complex. Strang Y(III)-compiexes such as Y-EDTMP are rapidly excreted without significant retention in soft tissues. Complexes of medium stability are in part transchelated to serum constituents resulting in a more complex distribution pattern. A low molecular fraction is responsible for the accumulation of radiometal in bone and bone metastases and another high molecular one represents the ternary complex which predominantly accumulates in the liver. As a conclusion from these bioinorganic studies the use of radiometal chelates in endoradiotherapy with metals having a small ionic radius (e.g. $^{166}$Ho, $^{169}$Er and $^{177}$Lu) will be superior to those with a large one as the unwanted liver accumulationwill be considerably reduced due to their low tendency to form ternary complexes with blood serum constituents.

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